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Publication numberUS6932962 B1
Publication typeGrant
Application numberUS 08/601,005
Publication dateAug 23, 2005
Filing dateDec 19, 1995
Priority dateDec 22, 1994
Fee statusLapsed
Also published asCA2206782A1, CA2206782C, CN1088580C, CN1170356A, DE69530325D1, DE69530325T2, EP0806940A1, EP0806940B1, WO1996019198A1
Publication number08601005, 601005, US 6932962 B1, US 6932962B1, US-B1-6932962, US6932962 B1, US6932962B1
InventorsKjell Bäckström, Magnus Dahlbäck, Ann Johansson, Göran Källstrand, Elisabet Lindqvist
Original AssigneeAstrazeneca Ab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
for use in pressurized metered dose inhalers (pMDI's); surfactants such as decyl glucoside or dodecyl maltoside
US 6932962 B1
Abstract
Aerosol formulations suitable for use in pressurised metered dose inhalers comprise a hydrofluoroalkane propellant, an medicament for inhalation and a surfactant which is a a C8–C16 fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide.
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Claims(53)
1. A pharmaceutical aerosol formulation comprising a hydrofluoroalkane (HFA) propellant; a physiologically effective amount of a medicament for inhalation; and an alkyl saccharide surfactant, wherein the medicament and the surfactant are suspended in the propellant as a finely divided powder.
2. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is selected from the group consisting of an alkyl glucoside and an alkyl maltoside.
3. A pharmaceutical aerosol formulation as claimed in claim 2, wherein the surfactant is selected from the group consisting of decyl glucoside and dodecyl maltoside.
4. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the formulation comprises a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227), or 1,1-difluoroethane (P152a).
5. The pharmaceutical aerosol formulation as claimed in claim 4, wherein the surfactant is decyl glucoside.
6. The pharmaceutical aerosol formulation as claimed in claim 4, wherein the surfactant is dodecyl maltoside.
7. A pharmaceutical aerosol formulation as claimed in claim 4, wherein the formulation comprises a propellant mixture comprising 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227).
8. A pharmaceutical aerosol formulation as claimed in claim 7, wherein the formulation comprises a density-matched propellant mixture of 1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227).
9. The pharmaceutical aerosol formulation as claimed in claim 7, wherein the surfactant is decyl glucoside.
10. The pharmaceutical aerosol formulation as claimed in claim 7, wherein the surfactant is dodecyl maltoside.
11. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the medicament is selected from the group consisting of a β2-adrenoreceptor agonist, an anticholinergic bronchodilator, and a glucocorticosteroid.
12. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the medicament is selected from the group consisting of salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol, procaterol, broxaterol, picumeterol, mabuterol, ipratropium bromide, beclomethasone, fluticasone, budesonide, tipredane, dexamethasone, betamethasone, fluocinolone, triamcinolone acetonide, mometasone, and pharmacologically acceptable esters and salts thereof.
13. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the medicament is selected from the group consisting of anti-allergic medicaments, expectorants, mucolytics, antihistamines, cyclooxygenase inhibitors, leukotriene synthesis inhibitors, leukotriene antagonists, phospholipase-A2 (PLA2) inhibitors, platelet aggregating factor (PAF) antagonists, prophylactics of asthma, antiarrhythmic medicaments, tranquilisers, cardiac glycosides, hormones, anti-hypertensive medicaments, antidiabetic medicaments, antiparasitic medicaments, anticancer medicaments, sedatives, analgesic medicaments, antibiotics, antirheumatic medicaments, immunotherapeutic agents, antifungal medicaments, antihypotension medicaments, vaccines, antiviral medicaments, proteins, peptides, vitamins, cell surface receptor blockers, antioxidants, free radical scavengers, and organic salts of N,N′-diacetylcystine.
14. A pharmaceutical aerosol formulation as claimed in claim 1, including ethanol in an amount of up to 20% by weight of propellant and surfactant.
15. A pharmaceutical aerosol formulation as claimed in claim 1, including ethanol in an amount of up to 5% by weight of propellant and surfactant.
16. A pharmaceutical aerosol formulation as claimed in claim 1, further comprising a substance selected from the group consisting of adjuvants, carriers, flavouring agents, buffers, antioxidants and chemical stabilisers.
17. A pharmaceutical aerosol formulation as claimed in claim 1, wherein at least 50% of the medicament consists of particles having a diameter of 0.01–10 microns.
18. A pharmaceutical aerosol formulation as claimed in claim 17, wherein at least 70% of the medicament consists of particles having a diameter of 0.01–10 microns.
19. A pharmaceutical aerosol formulation as claimed in claim 17, wherein at least 90% of the medicament consists of particles having a diameter of 0.01–10 microns.
20. A pharmaceutical aerosol formulation as claimed in claim 1, wherein at least 50% of the medicament consists of particles having a diameter of 0.1–6 microns.
21. A pharmaceutical aerosol formulation as claimed in claim 20, wherein at least 70% of the medicament consists of particles having a diameter of 0.01–6 microns.
22. A pharmaceutical aerosol formulation as claimed in claim 20, wherein at least 90% of the medicament consists of particles having a diameter of 0.01–6 microns.
23. A pharmaceutical aerosol formulation as claimed in claim 1, wherein at least 50% of the medicament consists of particles having a diameter of 0.1–5 microns.
24. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the concentration of medicament in the formulation is 0.1 mg/ml to 25 mg/ml.
25. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the ratio of surfactant to medicament is in the range of 1:50 to 1:0.2.
26. A pharmaceutical aerosol formulation as claimed in claim 1, the formulation comprising a physiologically effective amount of each of a β2-adrenoreceptor agonist and a glucocorticosteriod.
27. A pharmaceutical aerosol formulation as claimed in claim 26, further comprising a physiologically effective amount of an anticholinergic bronchodilator.
28. A pharmaceutical aerosol formulation as claimed in claim 1, the formulation comprising a physiologically effective amount of each of (a) formoterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) budesonide, or a salt, ester, solvate, or solvate of a salt or ester thereof.
29. A pharmaceutical aerosol formulation as claimed in claim 1, the formulation comprising a physiologically effective amount of each of (a) formoterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) mometasone, or a salt ester, solvate, or solvate of a salt or ester therefor.
30. A pharmaceutical aerosol formulation as claimed in claim 1, the formulation comprising a physiologically effective amount of each of (a) formoterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) fluticasone, or a salt, ester, solvate, or solvate of a salt or ester thereof.
31. A pharmaceutical aerosol formulation as claimed in claim 1, the formulation comprising a physiologically effective amount of each of (a) salmeterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) fluticasone, or a salt, ester, solvate, or solvate of a salt or ester thereof.
32. The pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is decyl glucoside.
33. The pharmaceutical aerosol formulation as claimed in claim 1, wherein the surfactant is dodecyl maltoside.
34. A pharmaceutical aerosol formulation as claimed in claim 1, the formulation comprising a physiologically effective amount of each of (a) formoterol and (b) budesonide.
35. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the formulation comprises a physiologically effective amount of each of (a) an anticholinergic bronchodilator and (b) a β2-adrenoreceptor agonist.
36. A pharmaceutical aerosol formulation as claimed in claim 1, wherein the formulation comprises a physiologically effective amount of each of (a) an anticholinergic bronchodilator and (b) a glucocorticosteroid.
37. A method for the manufacture of a pharmaceutical aerosol formulation as claimed in claim 1, comprising the steps of:
providing a mixture of the medicament and the surfactant in a vessel;
adding hydrofluoroalkane (HFA) propellant to the vessel; and
mixing the propellant with the medicament/surfactant mixture to produce a medicament/surfactant/propellant mixture in which the medicament and the surfactant are suspended in the propellant as a finely divided powder.
38. The method of claim 37, further comprising the step of mixing additional HFA propellant with the medicament/surfactant/propellant mixture to produce a further mixture in which the medicament and the surfactant are suspended in propellant as a finely divided powder.
39. A method for the treatment of a patient in need of therapy with an inhaled medicament, comprising administering to said patient a therapeutically effective amount of a pharmaceutical aerosol formulation comprising a HFA propellant; a physiologically effective amount of a medicament for inhalation; and an alkyl saccharide surfactant, wherein the medicament and the surfactant are suspended in the propellant as a finely divided powder.
40. The method of claim 39, wherein the formulation comprises a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227), and 1,1-difluoroethane (P152a).
41. The method of claim 39, wherein the surfactant is selected from the group consisting of an alkyl glucoside and an alkyl maltoside.
42. The method of claim 39, wherein the medicament is selected from the group consisting of a β2-adrenoreceptor agonist, an anticholinergic bronchodilator, and a glucocorticosteroid.
43. The method of claim 39, wherein the medicament is selected from the group consisting of anti-allergic medicaments, expectorants, mucolytics, antihistamines, cyclooxygenase inhibitors, leukotriene synthesis inhibitors, leukotriene antagonists, phospholipase-A2 (PLA2) inhibitors, platelet aggregating factor (PAF) antagonists, prophylactics of asthma, antiarrhythmic medicaments, tranquilisers, cardiac glycosides, hormones, anti-hypertensive medicaments, antidiabetic medicaments, antiparasitic medicaments, anticancer medicaments, sedatives, analgesic medicaments, antibiotics, antirheumatic medicaments, immunotherapeutic agents, antifungal medicaments, antihypotension medicaments, vaccines, antiviral medicaments, proteins, peptides, vitamins, cell surface receptor blockers, antioxidants, free radical scavengers, and organic salts of N,N′-diacetylcystine.
44. The method of claim 39, wherein the ratio of surfactant to medicament is in the range of 1:50 to 1:0.2.
45. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of a β2-adrenoreceptor agonist and a glucocorticosteriod.
46. The method of claim 45, wherein the formulation further comprises a physiologically effective amount of an anticholinergic bronchodilator.
47. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) formoterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) budesonide, or a salt, ester, solvate, or solvate of a salt or ester thereof.
48. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) formoterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) mometasone, or a salt ester, solvate, or solvate of a salt or ester therefor.
49. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) formoterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) fluticasone, or a salt, ester, solvate, or solvate of a salt or ester thereof.
50. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) salmeterol, or a salt, ester, solvate, or solvate of a salt or ester thereof; and (b) fluticasone, or a salt, ester, solvate, or solvate of a salt or ester thereof.
51. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) formoterol and (b) budesonide.
52. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) an anticholinergic bronchodilator and (b) a β2-adrenoreceptor agonist.
53. The method of claim 39, wherein the formulation comprises a physiologically effective amount of each of (a) an anticholinergic bronchodilator and (b) a glucocorticosteroid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/SE95/01542 filed on Dec. 19, 1995.

FIELD OF THE INVENTION

The present invention relates to aerosol formulations suitable for use in pressurised metered dose inhalers (pMDI's). More particularly, it relates to a formulation including a hydrofluoroalkane (HFA) propellant and a particularly suitable surface active-dispersing agent.

BACKGROUND OF THE INVENTION

Medicaments for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. One widely used method for dispensing such an aerosol formulation involves making a suspension formulation of the medicament as a finely divided powder in a liquefied gas known as a propellant. Pressurised metered dose inhalers, or (pMDI's) are normally used to dispense such formulations to a patient. Surface active agents, or surfactants, are commonly included in order to aid dispersion of the medicament in the propellant and to prevent aggregation of the micronised medicament particles, and to improve lubrication of the valve.

Until recently, chlorofluorocarbon-containing propellants (CFC's) were accepted for use in all pharmaceutical aerosol formulations. Typical surfactant dispersing agents used in the CFC formulations were for example sorbitantrioleate, oleic acid, lecithines, and ethanol. Since CFC's have been implicated in the destruction of the ozone layer, a new generation of propellants has emerged to take their place.

Hydrofluoroalkane (HFA) propellants for example 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) and 1,1-difluoroethane (P152a) are today considered to be the most promising new propellants. Not only are they environmentally acceptable, but they also have low toxicity and vapour pressures suitable for use in aerosols. However, the surfactants commonly used with the CFC formulations are not necessarily suitable for use with the new generation of propellants. Various alternative surfactants have been proposed.

For example, WO 92/00061 discloses polyethoxylated surfactant for use with hydrofluorocarbon propellants. WO 91/11173 discloses fluorinated surfactants. WO 91/14422 discloses perfluorinated carboxylic acid propellants for use with hydrofluorocarbon propellants. WO 92/00107 discloses the use of a 1,1,1,2-tetrafluoroethane-soluble surfactant with 1,1,1,2-tetrafluoroethane propellant.

SUMMARY OF THE INVENTION

It has now been found that certain specific classes of surfactant are particularly suitable for use with the new generation of propellant.

Accordingly, the present invention provides a pharmaceutical aerosol formulation comprising a hydrofluoroalkane propellant or a mixture of hydrofluoroalkane propellants, a physiologically effective amount of a medicament for inhalation and a surfactant selected from a C8–C16 fatty acid or salt thereof, a bile salt, a phospholipid or an alkyl saccharide.

The surfactants employed in the present invention give fine dispersions in the new propellants, with good stability. The inventive formulations are therefore useful for administering inhalable medicaments.

Of the fatty acid surfactants and salts thereof, C8–C16 fatty acids salts are preferred. Examples of preferred fatty acid salts are sodium, potassium and lysine salts of caprylate (C8), caprate (C10), laurate (C12) and myristate (C14). As the nature of the counterion is not of special significance, any of the salts of the fatty acids are potentially useful. A particularly preferred fatty acid salt is sodium caprate.

Suitable bile salts may be for example salts of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid.

Of the bile salts, trihydroxy bile salts are preferred. More preferred are the salts of cholic, glycocholic and taurocholic acids, especially the sodium and potassium salts thereof. The most preferred bile salt is sodium taurocholate.

Suitable phospholipids may be for example single-chain phospholipids, for example lysophosphatidylcholines, lysophosphatidylglycerols, lysophosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylserines or double-chain phospholipids, for example diacylphosphatidylcholines, diacylphosphatidylglycerols, diacylphosphatidylethanolamines, diacylphosphatidylinositols and diacylphosphatidylserines.

Of the phospholipids, diacylphosphatidylglycerols and diacylphosphatidylcholines are preferred, for example dioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine.

Suitable alkyl saccharides may be for example alkyl glucosides or alkyl maltosides, for example decyl glucoside and dodecyl maltoside.

The most preferred surfactants are bile salts.

The propellant may comprise for example one or more of 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) and 1,1-difluoroethane (P152a), optionally in admixture with one or more other propellants. Prefereably the propellant comprises 1,1,1,2-tetrafluoroethane (P134a) or 1,1,1,2,3,3,3-heptafluoropropane (P227), or a mixture of P134a and P227, for example a density-matched mixture of P134a and P227.

In addition to medicament, propellant and surfactant, a small amount of ethanol (normally up to 5% but possibly up to 20%, by weight) may be included in the formulations of the present invention. Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion.

Medicaments suitable for inclusion in the formulation of the present invention are any which may be delivered by inhalation. Suitable inhalable medicaments may include for example β2-adrenoreceptor agonists for example salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol, procaterol, broxaterol, picumeterol, TA-2005, mabuterol and the like, and their pharmacologically acceptable esters and salts; anticholinergic bronchodilators for example ipratropium bromide and the like; glucocorticosteroids for example beclomethasone, fluticasone, budesonide, tipredane, dexamethasone, betamethasone, fluocinolone, triamcinolone acetonide, mometasone, and the like, and their pharmacologically acceptable esters and salts; anti-allergic medicaments for example sodium cromoglycate and nedocromil sodium; expectorants; mucolytics; antihistamines; cyclooxygenase inhibitors; leukotriene synthesis inhibitors; leukotriene antagonists, phospholipase-A2 (PLA2) inhibitors, platelet aggregating factor (PAF) antagonists and prophylactics of asthma; antiarrhythmic medicaments, tranquilisers, cardiac glycosides, hormones, anti-hypertensive medicaments, antidiabetic- antiparasitic- and anticancer- medicaments, sedatives and analgesic medicaments, antibiotics, antirheumatic medicaments, immunotherapies, antifungal and antihypotension medicaments, vaccines, antiviral medicaments, proteins, peptides, vitamins and others, for example cell surface receptor blockers, antioxidants, free radical scavengers and organic salts of N,N′-diacetylcystine.

Combinations of medicaments are also suitable, for example a combination of formoterol and budesonide.

The medicaments may be used in the form of salts or esters or solvates (hydrates), where appropriate.

Other ingredients may be added into the formulation of the present invention, if desired. Such ingredients may be for example other pharmaceutically active agents, adjuvants, carriers, flavouring agents, buffers, antioxidants, chemical stabilisers and the like.

Preferably the surfactant and medicament are present in the present invention in a ratio of approximately 1:50 to 1:0.2. The preferred concentration of medicament in the formulations of the present invention is 0.1 mg/ml to 25 mg/ml.

“A medicament for inhalation” means a medicament which is suitable for inhalation and which consists largely of particles in a size range appropriate for maximal deposition in the lower respiratory tract (i.e., under 10 microns). Therefore as much as possible of the medicament preferably consists of particles having a diameter of less than 10 microns, for example 0.01–10 microns or 0.1–6 microns, for example 0.1–5 microns. Preferably at least 50% of the medicament consists of particles within the desired size range. For example at least 60%, preferably at least 70%, more preferably at least 80% and most preferably at least 90% of the medicament consists of particles within the desired size range.

Therefore, the medicament for use in the present invention may have to be processsed prior to inclusion in the formulations, in order to produce particles in the desired size range. For example the medicament may be micronised, for example out in a suitable mill, for example a jet mill. Alternatively, particles in the desired particle range may be obtained by for example spray drying or controlled crystallisation methods, for example crystallisation using supercritical fluids.

Preferably, the surfactant for use in the present invention is also in the desired particle size range.

Where the surfactant and medicament are both micronised, they may be dry mixed and then micronised together, or they may be micronised separately and then mixed. The propellant and optional ethanol may be added thereafter, in one or more than one step.

Alternatively a portion of the micronised surfactant may be cold-mixed with a portion of the propellant and optional ethanol, whereafter the micronised medicament may be added. After mixing in of the medicament the remaining surfactant and propellant and optional ethanol may be added and the suspension filled into appropriate containers.

The aerosol formulation of the present invention is useful for the local or systemic treatment of diseases and may be administered for example via the upper and lower respiratory tract, including by the nasal route. As such the present invention also provides said aerosol formulation for use in therapy; the use of the aerosol formulation in the manufacture of a medicament for the treatment of diseases via the respiratory tract; and a method for the treatment of a patient in need of therapy, comprising administering to said patient a therapeutically effective amount of the aerosol formulation of the present invention.

The following Examples are intended to illustrate, but not limit, the invention:

Formulations of various medicaments in P134a and/or P227 with different surfactants were prepared in order to assess the quality of the suspensions formed. In the following examples the quality of the suspension is rated as “acceptable” or “good”. An acceptable suspension is characterised by one or more of slow settling or separation, ready re-dispersion, little flocculation, and absence of crystallisation or morphology changes, such that the dispersion is sufficiently stable to give a uniform dosing. A good dispersion is even more stable.

EXAMPLE 1

Micronised formoterol fumarate (1 part) and micronised sodium taurocholate (2 parts) (total 5 mg) were added to a plastic coated glass bottle. The bottle was chilled to approximately 40° C. with a mixture of carbon dioxide ice and isopropanol, and 10 ml chilled P134a (at approximately 40° C.) was added. The bottle was sealed with a metering valve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLE 2

Micronised budesonide (10 parts) and micronised sodium taurocholate (2 parts) (total 5 mg) were added to a plastic coated glass bottle. The bottle was chilled to approximately 40° C. with a mixture of carbon dioxide ice and isopropanol, and 10 ml chilled P134a (at approximately 40° C.) was added. The bottle was sealed with a metering valve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLE 3

Micronised salbutamol sulphate (10 parts) and micronised sodium taurocholate (2 parts) (total 5 mg) were added to a plastic coated glass bottle. The bottle was chilled to approximately 40° C. with a mixture of carbon dioxide ice and isopropanol, and 10 ml chilled P134a (at approximately −40° C.) was added. The bottle was sealed with a metering valve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLE 4

Micronised ipratropium bromide (1 part) and micronised sodium taurocholate (2 parts) (total 5 mg) were added to a plastic coated glass bottle. The bottle was chilled to approximately 40° C. with a mixture of carbon dioxide ice and isopropanol, and 10 ml chilled P134a (at approximately 40° C.) was added. The bottle was sealed with a metering valve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLES 5–8

Examples 14 were repeated, substituting propellant P227 for P134a. In all cases, good suspensions formed.

EXAMPLES 9–16

Examples 1–8 were repeated with the following addition: ethanol, approximately 650 μl, was added to the chilled bottle before sealing with the metering valve. In all cases, acceptable suspensions formed.

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Classifications
U.S. Classification424/46, 424/45, 514/975
International ClassificationA61K47/44, A61K9/12, A61K9/14, A61K47/28, A61K47/26, A61K9/72, A61K, A61K47/12, A61K47/24, A61K47/00, A61K9/00, A61P1/00
Cooperative ClassificationY10S514/975, A61K9/008, A61K9/0073
European ClassificationA61K9/00M20B6, A61K9/00M20B
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